Association between urinary phthalates and phthalate metabolites and cancer risk: A systematic review and meta-analysis.

Phthalates, widely utilized in industrial products, are classified as endocrine-disrupting chemicals (EDCs). Although certain phthalate and their metabolites have been implicated in cancer development, the reported findings have exhibited inconsistencies. Therefore, we conducted the comprehensive literature search to assess the association between phthalate and their metabolites and cancer risk by identifying original studies measuring phthalates or their metabolites and reporting their correlation with cancer until July 4, 2023. The Odds Ratios (ORs) and corresponding 95% confidence intervals (CIs) were extracted and analyzed to estimate the risk. Pooled data from eleven studies, including 3101 cancer patients and 6858 controls, were analyzed using a fixed- or random-effects model based on heterogeneity tests. When comparing extreme categories of different phthalates and their metabolites, we observed a significant association between urinary phthalates and phthalate metabolites (MEHHP, MECPP, DBP and MBzP) and cancer risk. The findings of our meta-analysis reinforce the existing evidence that urinary phthalates and phthalate metabolites is strongly associated with cancer development. Further investigations are warranted to elucidate the underlying mechanisms of this association. These results may offer novel insights into cancer development.

MiR-145-5p reduced ANG II-induced ACE2 shedding and the inflammatory response in alveolar epithelial cells by targeting ADAM17 and inhibiting the AT1R/ADAM17 pathway.

The excessive elevation of angiotensin II (ANG II) is closely associated with the occurrence and development of aortic dissection (AD)-related acute lung injury (ALI), through its binding to angiotensin II receptor type I (AT1R). MiR-145-5p is a noncoding RNA that can be involved in a variety of cellular physiopathological processes. Transfection with miR-145-5p was found to downregulated the expression of A disintegrin and metalloprotease 17 (ADAM17) and reduced the levels of angiotensin-converting enzyme 2 (ACE2) in lung tissue, while concurrently increasing plasma ACE2 levels in the AD combined with ALI mice. ADAM17 was proved to be a target of miR-145-5p. Transfection with miR-145-5p decreased the shedding of ACE2 and alleviated the inflammatory response induced by ANG II through targeting ADAM17 and inhibiting the AT1R/ADAM17 pathway in A549 cells. In conclusion, our present study demonstrates the role and mechanism of miR-145-5p in alleviating ANG II-induced acute lung injury, providing a new insight into miRNA therapy for reducing lung injury in patients with aortic dissection.

Development and validation of a risk prediction model for postoperative gastrointestinal complications in patients undergoing aortic arch surgery.

BACKGROUND: Postoperative gastrointestinal complications (GICs) were potentially fatal to patients who underwent aortic arch surgery. The aim of this study was to construct a prediction model of GICs. METHODS: We retrospectively studied the medical records of 3063 patients who underwent aortic arch surgery. Patients were randomly divided into derivation and validation cohorts at a ratio of 4:1. A nomogram was constructed in the derivation cohort. RESULTS: A total of 157 patients with GICs were identified. In the derivation cohort, multivariate analysis identified six predictors of GICs including hypertension, ASA classification, preinduction MAP, aortic cross-clamp time, CPB time, and intraoperative transfusion of red blood cells. Compared with the patients without GICs, the patients with GICs had higher mortality, and longer ICU and hospital stays. We also divided the patients into four intervals according to the risk of GICs. CONCLUSIONS: This study developed a reliable prediction model of GICs after aortic arch surgery. This prediction model had been well verified in our research centre, and further external verification was required before it can be recommended for clinical application.

Secoisolariciresinol diglucoside regulates estrogen receptor expression to ameliorate OVX-induced osteoporosis.

OBJECTIVE: Secoisolariciresinol diglucoside (SDG) is a phytoestrogen that has been reported to improve postmenopausal osteoporosis (PMOP) caused by estrogen deficiency. In our work, we aimed to investigate the mechanism of SDG in regulating the expressions of ERs on PMOP model rats. METHODS: Ovariectomization (OVX) was used to establish PMOP model in rats. The experiment was allocated to Sham, OVX, SDG and raloxifene (RLX) groups. After 12-week treatment, micro-CT was used to detect the transverse section of bone. Hematoxylin and Eosin staining and Safranine O-Fast Green staining were supplied to detect the femur pathological morphology of rats. Estradiol (E2), interleukin-6 (IL-6), bone formation and bone catabolism indexes in serum were detected using ELISA. Alkaline phosphatase (ALP) staining was used to detect the osteogenic ability of chondrocytes. Immunohistochemistry and Western blot were applied to detect the protein expressions of estrogen receptors (ERs) in the femur of rats. RESULTS: Compared with the OVX group, micro-CT results showed SDG could lessen the injury of bone and improve femoral parameters, including bone mineral content (BMC) and bone mineral density (BMD). Pathological results showed SDG could reduce pathological injury of femur in OVX rats. Meanwhile, SDG decreased the level of IL-6 and regulated bone formation and bone catabolism indexes. Besides, SDG increased the level of E2 and conversed OVX-induced decreased the expression of ERα and ERß. CONCLUSION: The treatment elicited by SDG in OVX rats was due to the reduction of injury and inflammation and improvement of bone formation index, via regulating the expression of E2 and ERs.

The efficacy and safety of some new GABAkines for treatment of depression: A systematic review and meta-analysis from randomized controlled trials.

Positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors, or GABAkines, play important roles in the treatment of depression, epilepsy, insomnia, and other disorders. Recently, some new GABAkines (zuranolone and brexanolone) have been administrated to patients with major depressive disorder (MDD) or postpartum depression (PPD) in randomized controlled trials (RCTs). This study aims to systematically review and examine the efficacy and safety of zuranolone or brexanolone for treatment of depression. A systematic literature retrieval was conducted through August 20, 2023. RCTs evaluating the efficacy and safety of zuranolone or brexanolone for treatment of depression were included. Eight studies (nine reports) were identified in the study. The percentages of patients with PPD achieving Hamilton Depression Rating Scale (HAM-D) response and remission were significantly higher after brexanolone or zuranolone administration compared with placebo at different points. The percentages of patients with MDD achieving HAM-D response and remission were significantly increased during the zuranolone treatment period compared with placebo. In addition, zuranolone caused more adverse events in patients with MDD compared with placebo. Our findings support the effects of brexanolone on improving the core symptoms of depression in patients with PPD, and the potential of zuranolone in treating patients with MDD or PPD.

Assessing the effectiveness of massive open online courses on improving clinical skills in medical education in China: A meta-analysis.

Massive Open Online Courses (MOOCs) are a new phenomenon in education worldwide. In China, MOOCs have been widely used in medical courses. However, the effects of MOOCs on improving clinical skills are controversial. Therefore, we conducted the study to verify whether the application of MOOCs in medical courses can improve participants' clinical skills in China. A systematic literature search was carried out using the PubMed, Embase, Web of Science, CNKI and Wanfang databases according to the predetermined criteria. The Hedges' g and its corresponding 95% confidence interval were selected to assess the effects of MOOCs on participants' clinical skills. Subgroup analyses, sensitivity analysis and publication bias test were performed in the study. A total of thirty-two records (thirty-two studies) with 3422 participants were identified in our study. There was a significant improvement in clinical skill scores of participants in the MOOC group compared with the control group. Subgroup analyses showed similar results in different student groups. Our study supported the notion that the MOOC-based teaching method appeared to be a more effective method than the conventional teaching technique for the improvement of participants' clinical skills in China.

Benefits of topical indigo naturalis nanofibrous patch on psoriatic skin: A transdermal strategy for botanicals.

Indigo naturalis (IN) has been extensively used as a topical treatment for psoriasis. However, clinical applications of IN in ointment were hampered by its limited transdermal efficiency and dark stains. To address the aforementioned issues, nanopatches carrying IN were fabricated using poly(ε-caprolactone, PCL)/poly(ethylene oxide, PEO) and topically applied to psoriasiform skin. The ideal ratio of 5% PCL/PEO was established to be 80:20 (w/w), and 15% IN as payload was confirmed. Investigations on the three principal active components of IN release indicated that indirubin and tryptanthrin were released in bursts, while indigo was released in a limited and controlled manner. Further biological analyses confirmed a favorable biocompatibility of amphiphilic IN-PCL/PEO, which coincided with the intended therapeutic outcomes as measured by severity index scoring and pathological evaluations in vivo. The advantages of IN as nanopatches over ointment could be due to improved transdermal distribution of indirubin and tryptanthrin, resulting in effective management of epidermal hyperplasia and blood vessel remodeling. Meanwhile, due to the lower preservation of epidermal indigo, IN-PCL/PEO nanopatches caused no skin coloration. Similarly, during a 4-week topical treatment of IN-PCL/PEO nanopatches, the safety and anti-psoriatic benefits were obtained in an initial human test. The conversion of IN from topical cream to electrospun nanofibers opens up new avenues for bench-to-bedside translation of this herbal therapy and provides mechanistic insight into IN's roles in the management of psoriasis.

The risk factors of postoperative hypoxemia in patients with Stanford type A acute aortic dissection.

Hypoxemia is one of the most common complications in patients after Stanford type A acute aortic dissection surgery. The aim of this study was to investigate the association of circulating ANG II level with postoperative hypoxemia and to identify the risk factors for postoperative hypoxemia in Stanford type A acute aortic dissection patients. In this study, 88 patients who underwent Stanford type A acute aortic dissection surgery were enrolled. Postoperative hypoxemia is defined by the oxygenation index (OI). Perioperative clinical data were collected and the serum ANG II and sACE2 levels were measured. The differences in the basic characteristics, intraoperative details, biochemical parameters, laboratory test data and clinical outcomes were compared between the hypoxemia group and the non-hypoxemia group by univariate analysis. Multivariate logistic regression analysis was performed on the variables with P < .1 in univariate analysis or that were considered clinically important to identify risk factors for postoperative hypoxemia. Twenty-five patients (28.4%) were considered to have postoperative hypoxemia (OI ≤ 200 mm Hg). The ANG II concentration remained a risk factor associated with postoperative hypoxemia [OR = 1.018, 95% CI (1.003-1.034), P = .022]. The other risk factors remaining in the logistic regression model were BMI [OR = 1.417, 95% CI (1.159-1.733), P = .001] and cTnI [OR = 1.003, 95% CI (1.000-1.005), P = .032]. Elevated levels of ANG II, BMI and cTnI are risk factors for postoperative hypoxemia in patients with Stanford type A acute aortic dissection.

Synergistic effect and mechanism of cellulose nanocrystals and calcium ion on the film-forming properties of pea protein isolate.

The current serious environmental problems have greatly encouraged the design and development of food packaging materials with environmental protection, green, and safety. This study aims to explore the synergistic effect and corresponding mechanism of cellulose nanocrystals (CNC) and CaCl2 to enhance the film-forming properties of pea protein isolate (PPI). The combination of 0.5 % CNC and 4.5 mM CaCl2 resulted in a 76.6 % increase in tensile strength when compared with pure PPI-based film. Meanwhile, this combination effectively improved the barrier performance, surface hydrophobicity, water resistance, and biodegradability of PPI-based film. The greater crystallinity, viscoelasticity, lower water mobility, and improved protein spatial conformation were also observed in CNC/CaCl2 composite film. Compared with the control, the main degradation temperature of composite film was increased from 326.23 °C to 335.43 °C. The CNC chains bonded with amino acid residue of pea protein at specific sites via non-covalent forces (e.g., hydrogen bonds, Van der Waals forces). Meanwhile, Ca2+ promoted the ordered protein aggregation at suitable rate and degree, accompanied by the formation of more disulfide bonds. Furthermore, proper Ca2+ could strengthen the cross-linking and interaction between CNC and protein, thereby establishing a stable network structure. The prepared composite films are expected to be used for strawberry preservation.

Kaempferol inhibits SARS-CoV-2 invasion by impairing heptad repeats-mediated viral fusion.

BACKGROUND: The continuous evolution of SARS-CoV-2 has underscored the development of broad-spectrum prophylaxis. Antivirals targeting the membrane fusion process represent promising paradigms. Kaempferol (Kae), an ubiquitous plant flavonol, has been shown efficacy against various enveloped viruses. However, its potential in anti-SARS-CoV-2 invasion remains obscure. PURPOSE: To evaluate capabilities and mechanisms of Kae in preventing SARS-CoV-2 invasion. METHODS: To avoid interference of viral replication, virus-like particles (VLPs) constructed with luciferase reporter were applied. To investigate the antiviral potency of Kae, human induced pluripotent stem cells (hiPSC)-derived alveolar epithelial cells type II (AECII) and human ACE2 (hACE2) transgenic mice were utilized as in vitro and in vivo models, respectively. Using dual split protein (DSP) assays, inhibitory activities of Kae in viral fusion were determined in Alpha, Delta and Omicron variants of SARS-CoV-2, as well as in SARS-CoV and MERS-CoV. To further reveal molecular determinants of Kae in restricting viral fusion, synthetic peptides corresponding to the conserved heptad repeat (HR) 1 and 2, involved in viral fusion, and the mutant form of HR2 were explored by circular dichroism and native polyacrylamide gel electrophoresis. RESULTS: Kae inhibited SARS-CoV-2 invasion both in vitro and in vivo, which was mainly attributed to its suppressive effects on viral fusion, but not endocytosis, two pathways that mediate viral invasion. In accordance with the proposed model of anti-fusion prophylaxis, Kae functioned as a pan-inhibitor of viral fusion, including three emerged highly pathogenic coronaviruses, and the currently circulating Omicron BQ.1.1 and XBB.1 variants of SARS-CoV-2. Consistent with the typical target of viral fusion inhibitors, Kae interacted with HR regions of SARS-CoV-2 S2 subunits. Distinct from previous inhibitory fusion peptides which prevent the formation of six-helix bundle (6-HB) by competitively interacting with HRs, Kae deformed HR1 and directly reacted with lysine residues within HR2 region, the latter of which was considered critical for the preservation of stabilized S2 during SARS-CoV-2 invasion. CONCLUSIONS: Kae prevents SARS-CoV-2 infection by blocking membrane fusion and possesses a broad-spectrum anti-fusion ability. These findings provide valuable insights into potential benefits of Kae-containing botanical products as a complementary prophylaxis, especially during the waves of breakthrough infections and re-infections.

Effects of melatonin against acute kidney injury: A systematic review and meta-analysis.

INTRODUCTION: Melatonin is a hormone synthesized by the pineal gland, and has antioxidative effects in reducing acute kidney injury (AKI). In the past three years, an increasing number of studies have evaluated whether melatonin has a protective effect on AKI. The study systematically reviewed and assessed the efficacy and safety of melatonin in preventing AKI. MATERIAL AND METHODS: A systematic literature search was conducted in the PubMed, Embase, and Web of Science databases on February 15, 2023. Eligible records were screened according to the inclusion and exclusion criteria. The odds ratio and Hedges' gwith the corresponding 95% confidence intervals were selected to evaluate the effects of melatonin on AKI. We pooled extracted data using a fixed- or random-effects model based on a heterogeneity test. RESULTS: There were five studies (one cohort study and four randomized controlled trials) included in the meta-analysis. Although the glomerular filtration rate (GFR) may be significantly improved by melatonin, the incidence of AKI was not significantly decreased in the melatonin group compared with the control group in randomized controlled trials (RCTs). CONCLUSIONS: In our study, the present results do not support a direct effect of melatonin use on the reduction of AKI. More well-designed clinical studies with larger sample size are required in the future.

Survey on the Construction Status of Forensic Virtual Autopsy Laboratory and the Applicability of Laboratory Accreditation.

OBJECTIVES: To survey the development status and actual needs of virtual autopsy technology in China and to clarify the applicability of forensic virtual autopsy laboratory accreditation. METHODS: The questionnaire was set up included three aspects：(1) the current status of virtual autopsy technology development; (2) the accreditation elements such as personnel, equipment, entrustment and acceptance, methods, environmental facilities; (3) the needs and suggestions of practicing institutions. A total of 130 forensic pathology institutions were surveyed by online participation through the Questionnaire Star platform. RESULTS: Among the 130 institutions, 43.08% were familiar with the characteristics of virtual autopsy technology, 35.38% conducted or received training in virtual autopsy, and 70.77% have establishment needs (including maintenance). Relevant elements were suitable for laboratory accreditation. CONCLUSIONS: Virtual autopsy identification has gained social recognition. There is a demand for accreditation of forensic virtual autopsy laboratory. After the preliminary assessment, considering the characteristics and current situation of this technology, China National Accreditation Service for Conformity Assessment (CNAS) can first carry out the accreditation pilot of virtual autopsy project at large comprehensive forensic institutions with higher identification capability, and then CNAS can popularize the accreditation in a wide range when the conditions are suitable.

RNA polymerase I subunit RPA43 activates rRNA expression and cell proliferation but inhibits cell migration.

The products synthesized by RNA polymerase I (Pol I) play fundamental roles in several cellular processes, including ribosomal biogenesis, protein synthesis, cell metabolism, and growth. Deregulation of Pol I products can cause various diseases such as ribosomopathies, leukaemia, and solid tumours. However, the detailed mechanism of Pol I-directed transcription remains elusive, and the roles of Pol I subunits in rRNA synthesis and cellular activities still need clarification. In this study, we found that RPA43 expression levels positively correlate with Pol I product accumulation and cell proliferation, indicating that RPA43 activates these processes. Unexpectedly, RPA43 depletion promoted HeLa cell migration, suggesting that RPA43 functions as a negative regulator in cell migration. Mechanistically, RPA43 positively modulates the recruitment of Pol I transcription machinery factors to the rDNA promoter by activating the transcription of the genes encoding Pol I transcription machinery factors. RPA43 inhibits cell migration by dampening the expression of c-JUN and Integrin. Collectively, we found that RPA43 plays opposite roles in cell proliferation and migration except for driving Pol I-dependent transcription. These findings provide novel insights into the regulatory mechanism of Pol I-mediated transcription and cell proliferation and a potential pathway to developing anti-cancer drugs using RPA43 as a target.

Gilteritinib-induced severe immune-related enteritis: a possible case report.

Gilteritinib is currently approved in China for relapsed/refractory FLT3-mutated acute myeloid leukemia, and it is very important to monitor and report its adverse drug reaction (ADR) after post-marketing. This case report describes a patient who was diagnosed with acute myeloid leukemia harboring FLT3 mutations and developed a severe suspected immune-related enteritis during treatment with gilteritinib for maintenance therapy following allo-hematopoietic stem cell transplantation. According to the Naranjo probability scale, gilteritinib was defined as a 'possible' cause of ADR. Another suspicious inducement, graft-versus-host disease, can not be eluted and might represent a limitation in this case. To the best of our knowledge, this is the first report on gilteritinib-induced severe enteritis and will help physicians to keep vigilant, and detect and deal with time for possible ADR.

Chronic exposure to (2 R,6 R)-hydroxynorketamine induces developmental neurotoxicity in hESC-derived cerebral organoids.

(R,S)-ketamine (ketamine) has been increasingly used recreationally and medicinally worldwide; however, it cannot be removed by conventional wastewater treatment plants. Both ketamine and its metabolite norketamine have been frequently detected to a significant degree in effluents, aquatic, and even atmospheric environments, which may pose risks to organisms and humans via drinking water and aerosols. Ketamine has been shown to affect the brain development of unborn babies, while it is still elusive whether (2 R,6 R)-hydroxynorketamine (HNK) induces similar neurotoxicity. Here, we investigated the neurotoxic effect of (2 R,6 R)-HNK exposure at the early stages of gestation by applying human cerebral organoids derived from human embryonic stem cells (hESCs). Short-term (2 R,6 R)-HNK exposure did not significantly affect the development of cerebral organoids, but chronic high-concentration (2 R,6 R)-HNK exposure at day 16 inhibited the expansion of organoids by suppressing the proliferation and augmentation of neural precursor cells (NPCs). Notably, the division mode of apical radial glia was unexpectedly switched from vertical to horizontal division planes following chronic (2 R,6 R)-HNK exposure in cerebral organoids. Chronic (2 R,6 R)-HNK exposure at day 44 mainly inhibited the differentiation but not the proliferation of NPCs. Overall, our findings indicate that (2 R,6 R)-HNK administration leads to the abnormal development of cortical organoids, which may be mediated by inhibiting HDAC2. Future clinical studies are needed to explore the neurotoxic effects of (2 R,6 R)-HNK on the early development of the human brain.

Complexation between rice starch and cellulose nanocrystal from black tea residues: Gelatinization properties and digestibility in vitro.

In this work, cellulose nanocrystal (CNC) was extracted from black tea waste and its effects on the physicochemical properties of rice starch were explored. It was revealed that CNC improved the viscosity of starch during pasting and inhibited its short-term retrogradation. The addition of CNC changed the gelatinization enthalpy and improved the shear resistance, viscoelasticity, and short-range ordering of starch paste, which meant that CNC made the starch paste system more stable. The interaction of CNC with starch was analyzed using quantum chemistry methods, and it was demonstrated that the hydrogen bonds were formed between starch molecules and the hydroxyl groups of CNC. In addition, the digestibility of starch gels containing CNC was significantly decreased because CNC could dissociate and act as an inhibitor of amylase. This study further expanded the understanding of the interactions between CNC and starch during processing, which could provide a reference for the application of CNC in starch-based foods and the development of functional foods with a low glycemic index.

Risk Factors and Early Outcomes for Gastrointestinal Complications in Patients Undergoing Open Surgery for Type A Aortic Dissection.

BACKGROUND: Gastrointestinal complications need to be paid more attention, especially in critically ill patients. The purpose of this study was to identify the risk factors and short-term outcomes of gastrointestinal complications after open surgery for type A aortic dissection. METHODS: A retrospective single-institutional study including patients who underwent open surgery for type A aortic dissection during 2012-2020 was conducted. Univariate analysis and logistic regression analysis were used to identify risk factors associated with gastrointestinal complications. The related clinical outcomes were compared between the patients with and without gastrointestinal complications. RESULTS: Among the 2746 patients, 150 developed gastrointestinal complications. The development of gastrointestinal complications contributed to the higher rate of mortality (P = .008), longer stay in the intensive care unit (P < .001), and longer hospital stay (P < .001). Logistic regression analysis showed that age (odds ratio [OR] 1.020; 95% confidence interval [CI] 1.005-1.057; P = .011), American Society of Anesthesiologists classification greater than grade III (OR 1.724; 95%CI 1.179-2.521, P = .005), pre-induction mean arterial pressure (OR 0.978; 95%CI 0.965-0.990, P = .001), aortic cross-clamp time (OR 1.012; 95%CI 1.005-1.019, P = .001), cardiopulmonary bypass time (OR 1.007; 95%CI 1.002-1.011, P = .002), and intraoperative transfusion of red blood cells (OR 1.214; 95%CI 1.122-1.314, P = .001) were independent risk factors for gastrointestinal complications. CONCLUSIONS: The incidence of gastrointestinal complications after open surgery for type A aortic dissection was 5.5%, resulting in increased mortality and prolonged hospital stay. It is necessary to take suitable strategies to reduce the incidence of gastrointestinal complications.

Effects of primary angle-closure glaucoma on interhemispheric functional connectivity.

Background: Previous studies on primary angle-closure glaucoma (PACG) primarily focused on local brain regions or global abnormal brain activity; however, the alteration of interhemispheric functional homotopy and its possible cause of brain-wide functional connectivity abnormalities have not been well-studied. Little is known about whether brain functional alteration could be used to differentiate from healthy controls (HCs) and its correlation with neurocognitive impairment. Methods: Forty patients with PACG and 40 age- and sex-matched healthy controls were recruited for this study; resting-state functional magnetic resonance imaging (rs-fMRI), and clinical data were collected. We used the voxel-mirrored homotopic connectivity (VMHC) method to explore between-group differences and selected brain regions with statistically significant differences as regions of interest for whole-brain functional connectivity analysis. Partial correlation was used to evaluate the association between abnormal VMHC values in significantly different regions and clinical parameters, with with age and sex as covariates. Finally, the support vector machine (SVM) model was performed in classification prediction of PACG. Results: Compared with healthy controls, patients with PACG exhibited significantly decreased VMHC values in the lingual gyrus, insula, cuneus, and pre- and post-central gyri; no regions exhibited increased VMHC values. Subsequent functional connectivity analysis revealed extensive functional changes in functional networks, particularly the default mode, salience, visual, and sensorimotor networks. The SVM model showed good performance in classification prediction of PACG, with an area under curve (AUC) of 0.85. Conclusion: Altered functional homotopy of the visual cortex, sensorimotor network, and insula may lead to impairment of visual function in PACG, suggesting that patients with PACG may have visual information interaction and integration dysfunction.

Di-(2-ethylhexyl) phthalate exposure impairs cortical development in hESC-derived cerebral organoids.

Di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous environmental endocrine disruptor, is widely used in consumer products. Increasing evidence implies that DEHP influences the early development of the human brain. However, it lacks a suitable model to evaluate the neurotoxicity of DEHP. Using an established human cerebral organoid model, which reproduces the morphogenesis of the human cerebral cortex at the early stage, we demonstrated that DEHP exposure markedly suppressed cell proliferation and increased apoptosis, thus impairing the morphogenesis of the human cerebral cortex. It showed that DEHP exposure disrupted neurogenesis and neural progenitor migration, confirmed by scratch assay and cell migration assay in vitro. These effects might result from DEHP-induced dysplasia of the radial glia cells (RGs), the fibers of which provide the scaffolds for cell migration. RNA sequencing (RNA-seq) analysis of human cerebral organoids showed that DEHP-induced disorder in cell-extracellular matrix (ECM) interactions might play a pivotal role in the neurogenesis of human cerebral organoids. The present study provides direct evidence of the neurodevelopmental toxicity of DEHP after prenatal exposure.

Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids.

Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organoids to analyze the pathogenic effects caused by VPA exposure and critical signaling pathway. We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner. VPA exposure typically decreased the production of outer radial glia-like cells (oRGs), a subtype of NPCs contributing to mammalian neocortical expansion and delayed their fate toward upper-layer neurons. Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients. We also identified that VPA-mediated Wnt/ß-catenin signaling pathway activation is essential for sustaining cortical neurogenesis and oRGs output. Taken together, our study establishes the use of dorsal forebrain organoids as an effective platform for modeling VPA-induced teratogenic pathways involved in the cortical neurogenesis and oRGs output, which might contribute to ASD pathogenesis in the developing brain.